Hepatitis C virus (HCV) infection occurs in 30% of HIV-infected individuals and 90% of injection drug users (IDU) with HIV infection. Studies among drug non-users indicate that advanced HIV infection is associated with more rapid progression of HCV disease. However, as noted in the 2002 NIH Consensus Conference on Hepatitis C, these results may not apply to IDU, and the largest published study of HCV- infected IDU failed to demonstrate increased risk among HIV co-infected subjects. Therefore, further study of the natural history of HCV infection in IDU is needed. The Hepatitis C, HIV And Related Morbidity (CHARM) study at Boston University Medical Center was initiated in 2000 and comprises 378 IDU with HCV infection; 230 (61%) are HIV-infected. In univariate analysis of this prospective cohort, we have shown that HIV infection (p=0.04), black race (p=0.08) and Hispanic ethnicity (p=0.10) are potential risk factors for progression of liver disease, while a lower CD4 cell count confers significant additional risk among HIV/HCV co-infected IDU (p<0.01) and antiretroviral therapy (ART) is associated with decreased risk (p=0.09). These and other results from this work have been published in 6 articles and 14 abstracts; an additional 4 manuscripts and 2 abstracts have been submitted. With further follow-up, we will be able to determine factors independently associated with progression of HCV disease in IDU using multivariate analysis. The overall goal of the studies proposed in this revised application is identification of strategies to prevent the adverse outcomes associated with HIV/HCV co-infection among IDU. We have the following Specific Aims: 1) To define the independent effects of HIV infection and race/ethnicity on clinical progression of liver disease and liver-related mortality in HCV-infected IDU; 2) To define the independent effects of CD4 count, HIV viral load, and ART on clinical progression of liver disease and liver-related mortality in HIV/HCV co-infected IDU; 3) To examine the relationship between serologic markers of hepatic fibrosis and clinical progression of liver disease and liver-related mortality in HCV-infected IDU with and without HIV infection. These investigations will define the role of HIV infection in progression of HCV disease and guide HCV treatment and prevention strategies for IDU.